Project Abstract Background: Optic nerve head (ONH) biomechanics is thought to play a critical role in the pathophysiology of primary open angle glaucoma (POAG). ONH biomechanics is driven be the interactions between intraocular pressure (IOP), cerebrospinal fluid pressure (CSFP) and connective tissue structural stiffness (the combination of tissue architecture and material properties) in the ONH and sclera. Computational and experimental studies in animal models have suggested that strain (tissue stretch) in the ONH microenvironment is strongly influenced by the structural stiffness of the sclera and the morphology and density of the lamina cribrosa (LC). Experimental studies have shown that these structures also vary with the development of glaucoma, with age and across racial groups of African descent (AD) vs. European descent (ED) and may also be associated with variation in corneal thickness and rigidity. This is important since age, glaucoma severity, AD and corneal thickness and rigidity are the most consistent risk factors for OAG independent of IOP. The Objectives of this study are: 1) to discover how the morphology of the LC and scleral rigidity determine the mechanical behavior of the ONH in response to changes in IOP and CSFP and 2) to determine how differences in structural stiffness of the scleral, ONH and cornea seen in aging, with glaucoma and across racial groups are related to ONH strain. Design: This study will employ a novel resource, the Alabama Living Eye Project. This program affords access to brain-dead organ donors prior to organ procurement. Follow discussion and consent with the next-of-kin, an ocular exam with biometry will be performed, followed by the quantification of in-vivo ONH strain in response to changes in both IOP and CSFP using spectral domain optical coherence tomography (SDOCT). Following organ procurement, scleral structural stiffness will be measured with laser electronic speckle pattern interferometry and ONH microstructure will be quantified in digital 3D histologic episcopic reconstructions of the ONH. Multivariable models will be used to determine the impact of scleral rigidity and ONH morphology on ONH strain and if these relationships differ in aged and glaucomatous eyes, in eyes from AD or ED donors and with variations in corneal stiffness. Impact: This study provides the unique opportunity to link scleral and ONH biomechanics to clinical ocular imaging and biometrics data, and will elucidate the causative mechanisms related to the variation in ONH biomechanics seen with age, with glaucoma, across AD and ED groups and associated with measurement of corneal thickness and rigidity. Not only will this information inform the development of mechanistically relevant biomarkers for glaucoma susceptibility, understanding how scleral stiffness and ONH morphology modulate ONH biomechanics will guide the development of new non-IOP lowering glaucoma therapies targeted at altering strain-driven remodeling of the ONH. !